Histological evidence of redox system breakdown caused by superoxide dismutase 1 (SOD1) aggregation is common to SOD1-mutated motor neurons in humans and animal models
Histological evidence of redox system breakdown caused by superoxide dismutase 1 (SOD1) aggregation is common to SOD1-mutated motor neurons in humans and animal models
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DOI：
10.1007/s00401-003-0791-1
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发表时间：
2004-02-01
影响因子：
12.7
通讯作者：
Ohama, E
中科院分区：
文献类型：
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作者：
Kato, S;Saeki, Y;Ohama, E
活细胞产生活性氧（ROSs）。为了保护自己免受这些ROSs的伤害，细胞发展了包含超氧化物歧化酶1 （SOD1）的抗氧化系统和包含过氧化物歧化酶2 （Prx2，硫氧还蛋白过氧化物酶）和谷胱甘肽过氧化物酶1 （GPx1）的氧化还原系统：SOD1将超氧化物自由基转化为过氧化氢(H(2)O(2))，然后H(2)O(2)通过Prx2和GPx1直接调节氧化还原系统转化为无害的水（H(2)O）和氧（O(2)）。为了阐明体内SOD1突变的运动神经元中氧化还原系统（Prx2/GPx1）与SOD1相互作用的生物学意义，我们制备了一种针对Prx2的亲和纯化兔抗体，并研究了Prx2和GPx1在家族性肌萎缩性侧索硬化症（FALS）患者脊髓神经元Lewy体样透明包涵体（LBHIs）中的免疫组织化学定位，这些患者的SOD1基因的密码子126双碱基对缺失和密码子4的Ala- >Val替换，以及在表达人类SOD1的H46R和G93A突变的转基因大鼠中。sod1突变的FALS患者和转基因大鼠运动神经元中的LBHIs对Prx2和GPx1表现出相同的免疫反应性：LBHIs中含有抗Prx2和GPx1抗体的反应产物沉积。此外，SOD1和Prx2/GPx1的免疫反应性在包裹体中的定位相似：突变SOD1相关FALS患者和转基因大鼠的神经元LBHIs中Prx2/GPx1与SOD1共聚集明显。基于Prx2/GPx1直接调控氧化还原系统的事实，Prx2/GPx1与SOD1在神经元LBHIs中的共聚集可能导致氧化还原系统本身的破坏，从而放大突变SOD1介导的突变SOD1相关FALS患者和表达人类突变SOD1的转基因大鼠的毒性。
Living cells produce reactive oxygen species (ROSs). To protect themselves from these ROSs, the cells have developed both an antioxidant system containing superoxide dismutase 1 (SOD1) and a redox system including peroxiredoxin2 (Prx2, thioredoxin peroxidase) and glutathione peroxidase1 (GPx1): SOD1 converts superoxide radicals into hydrogen peroxide (H(2)O(2)), and H(2)O(2) is then converted into harmless water (H(2)O) and oxygen (O(2)) by Prx2 and GPx1 that directly regulate the redox system. To clarify the biological significance of the interaction of the redox system (Prx2/GPx1) with SOD1 in SOD1-mutated motor neurons in vivo, we produced an affinity-purified rabbit antibody against Prx2 and investigated the immunohistochemical localization of Prx2 and GPx1 in neuronal Lewy body-like hyaline inclusions (LBHIs) in the spinal cords of familial amyotrophic lateral sclerosis (FALS) patients with a two-base pair deletion at codon 126 and an Ala-->Val substitution at codon 4 in the SOD1 gene, as well as in transgenic rats expressing human SOD1 with H46R and G93A mutations. The LBHIs in motor neurons from the SOD1-mutated FALS patients and transgenic rats showed identical immunoreactivities for Prx2 and GPx1: the reaction product deposits with the antibodies against Prx2 and GPx1 were localized in the LBHIs. In addition, the localizations of the immunoreactivities for SOD1 and Prx2/GPx1 were similar in the inclusions: the co-aggregation of Prx2/GPx1 with SOD1 in neuronal LBHIs in mutant SOD1-related FALS patients and transgenic rats was evident. Based on the fact that Prx2/GPx1 directly regulates the redox system, such co-aggregation of Prx2/GPx1 with SOD1 in neuronal LBHIs may lead to the breakdown of the redox system itself, thereby amplifying the mutant SOD1-mediated toxicity in mutant SOD1-linked FALS patients and transgenic rats expressing human mutant SOD1.